Tumor metastasis is the major cause of death of cancer patients. Thus, prevention of tumor metastasis will significantly increase the survival rate of cancer patients, allow more moderate radiation or chemotherapy with less side- effects, and control the progression of tumors. One critical step of tumor metastasis is tumor cell migration and invasion. In this application, we focus on a new group of small molecules, the migrastatin analogues. We have shown that these small molecules are potent inhibitors of the migration of metastatic tumor cells, but not normal primary cells. We have shown that two of these migrastatin analogues reduced mouse breast tumor metastasis in a mouse model. We will perform preclinical discovery research and eventually develop these migrastatin analogues for cancer treatment/prevention. We have proposed three specific aims in this application. In the specific aim 1, we will focus on the molecular mechanism by which migrastatin analogues inhibit tumor cell migration. In the specific aim 2, we will examine the role of the target protein of migrastatin analogues in breast tumor cell migration, invasion, and metastasis. In the specific aim 3, we will investigate the effect of migrastatin analogues on the metastasis of human breast cancer cells in immune-compromised nude mice. The success of our study will provide a new therapeutic for cancer treatment, specifically for metastasis prevention. PUBLIC HEALTH RELEVANCE: The proposal investigates potential therapeutics for treatment of metastatic breast cancer. The spread or recurrence of breast cancer is every breast cancer patient's worst fear. Unfortunately, there is currently no curative treatment for breast cancer once it has metastasized. Therefore, there is a tremendous need for new treatments for metastatic (advanced stage) breast cancer. Since tumor cell migration is essential for breast tumor metastasis, cell migration inhibitors can be developed as new drugs to treat breast cancers. The migrastatin analogues hold much promise.